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Benzisoxazole spiropyrimidine triketone compounds and preparation method and use

A compound and mixture technology, applied in organic chemistry methods, organic chemistry, pharmaceutical formulations, etc., can solve problems such as limitations, unsatisfactory metabolic properties, and large clinical overdose, and achieve good druggability and excellent in vivo metabolic properties.

Active Publication Date: 2022-08-02
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, these spiropyrimidine triketone compounds such as AZD0914 still have the problems of weak antibacterial activity and unsatisfactory metabolic properties, which lead to large clinical overdose, which limits their possibility as a drug for treating systemic infections to a certain extent.

Method used

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  • Benzisoxazole spiropyrimidine triketone compounds and preparation method and use
  • Benzisoxazole spiropyrimidine triketone compounds and preparation method and use
  • Benzisoxazole spiropyrimidine triketone compounds and preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Example 1: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(5-oxo-4-oxo-6-azaspiro[2.4]heptan-6-yl )-1,2,4,4a-tetrahydro-2'H,6H-spiro[isoxazole[4,5-g][1,4]oxazine[4,3-a]quinoline-5, 5'-Pyrimidine]-2',4',6'(1'H,3'H)-trione (Compound 1)

[0111] (a) 1-((((5-(1,3-dioxolan-2-yl)-6,7-difluorobenzo[d]isoxazol-3-yl)amino)methyl)- 1-Cyclopropanol (I-3-1)

[0112]

[0113] Intermediate A (1 g, 4.048 mmol) was added to 20 ml of N,N-dimethylformamide, stirred to dissolve, N-chlorosuccinimide (650 mg, 4.868 mmol) was added at room temperature, and it was raised to The reaction was carried out at 40 °C for 30 min, and TLC (Thin Layer Chromatography) monitored the completion of the reaction. The reaction solution was brought to 0 °C, 1-aminomethyl-1-cyclopropanol (1.06 g, 12.144 mmol) was slowly added, and the reaction was returned to room temperature for 1 h. , TLC monitoring reaction is complete, add cesium carbonate (4.567g, 12.144mmol), raise to 60 ℃ reaction 2h, TLC monitoring reacti...

Embodiment 2

[0126] Example 2: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(6-oxo-2,5-dioxo-7-azaspiro[3.4]octane- 7-yl)-1,2,4,4a-tetrahydro-2'H,6H-spiro[isoxazo[4,5-g][1,4]oxazine[4,3-a]quinoline -5,5'-Pyrimidine]-2',4',6'(1'H,3'H)-trione (Compound 2)

[0127] (a) 3-(((5-(1,3-dioxolan-2-yl)-6,7-difluorobenzo[d]isoxazol-3-yl)amino)methyl)oxy Heterobutanol (I-3-2)

[0128]

[0129] According to the synthesis method of intermediate I-3-1, intermediate A (1.2 g, 4.857 mmol), N-chlorosuccinimide (778 mg, 5.828 mmol), 3-(aminomethyl)oxane Butanol (1.25 g, 12.142 mmol) and cesium carbonate (4.748 g, 14.571 mmol) were used as starting materials to synthesize 1-(((5-(1,3-dioxolan-2-yl)-6,7-diol Fluorobenzo[d]isoxazol-3-yl)amino)methyl)oxetanol 949mg, white solid, yield 59.5%, 1 H NMR(400MHz, DMSO)δ8.08(d,J=5.7Hz,1H),7.41(t,J=5.7Hz,1H),6.09(s,1H),6.01(s,1H),4.48(dd , J=15.1, 6.6Hz, 4H), 4.12–3.99 (m, 4H), 3.55 (d, J=5.8Hz, 2H).

[0130] (b) 7-(5-((1,3-dioxolan-2-yl)-6,7-difluorobenzo[d]isoxazol-3...

Embodiment 3

[0142] Example 3: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(6-oxo-5-oxo-7-azaspiro[3.4]octan-7-yl )-1,2,4,4a-tetrahydro-2'H,6H-spiro[isoxazole[4,5-g][1,4]oxazine[4,3-a]quinoline-5, 5'-Pyrimidine]-2',4',6'(1'H,3'H)-trione (Compound 3)

[0143] (a) 1-(((5-(1,3-dioxolan-2-yl)-6,7-difluorobenzo[d]isoxazol-3-yl)amino)methyl) ring Butanol (I-3-3)

[0144]

[0145] According to the synthesis method of intermediate I-3-1, intermediate A (750 mg, 3.036 mmol), N-chlorosuccinimide (527 mg, 3.947 mmol), 1-(aminomethyl)cyclobutanol ( 675 mg, 6.679 mmol) and cesium carbonate (3.957 g, 12.144 mmol) were used as starting materials to synthesize 1-(((5-(1,3-dioxolan-2-yl)-6,7-difluorobenzo[ d] Isoxazol-3-yl)amino)methyl)cyclobutanol 710mg, white solid, yield 72%, 1 H NMR (400MHz, DMSO) δ 8.15 (d, J=5.9Hz, 1H), 7.23 (t, J=5.4Hz, 1H), 6.08 (s, 1H), 5.27 (s, 1H), 4.11–3.99 (m, 4H), 3.34 (d, J=5.6 Hz, 2H), 2.12–1.92 (m, 4H), 1.72–1.45 (m, 2H).

[0146] (b) 7-(5-((1,3-dioxolan-2-yl)-6,7-difluo...

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Abstract

The invention discloses a benzisoxazole spiropyrimidine trione compound, a preparation method and application thereof, and the structure is shown in formula I. In the formula, the definition of each substituent is as described in the specification and claims. The benzisoxazole spiropyrimidine trione compounds of the invention have higher antibacterial activity in vitro and in vivo and better metabolic properties.

Description

technical field [0001] The present invention relates to a spiropyrimidine trione compound containing benzisoxazole group, its pharmaceutical composition, its preparation method and use in anti-infective medicine. Background technique [0002] With the widespread use and even abuse of antibacterial drugs, the multidrug resistance of pathogenic bacteria has become a serious problem that threatens human health. A series of drug-resistant pathogens represented by multidrug-resistant Staphylococcus aureus MRSA, It brings great challenges to clinical treatment. Although some new antibacterial drugs such as linezolid and daptomycin have been launched in recent years, which can effectively control the infection of gram-positive bacteria such as MRSA, but with more than 10 years of clinical application, bacteria have begun to slow down these drugs. Slowly producing resistant strains. Therefore, the development of novel antibacterial drugs with novel mechanism of action, unique stru...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/22C07D519/00C07D413/04C07D413/14C07D498/10C07D317/30C07D261/20A61K31/5386A61P31/04
CPCC07D261/20C07D317/30C07D413/04C07D413/14C07D498/10C07D498/22C07D519/00C07B2200/07
Inventor 杨玉社张银勇石程辉陈乾
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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